A major problem in developing pharmaceutical formulations is the poor solubility of pharmaceutical actives in water or any other commonly used medium and the subsequent poor bioavailability. To solve this problem different approaches have been taken which include developing suspensions, solubilizing in organic solvents, using salts of the drugs, developing prodrugs and using different types of drug delivery systems. Further, the insolubility of solid drug forms in common media such as water poses a major challenge because of the resulting low bioavailability of the active ingredients.
Many methods for solubilizing drugs have been developed that are based on the use of solvents or solubility enhancers, surfactants, complexation agents, or complex drug carriers. Surfactants and complexing agents have drawbacks of toxicity, and rapid precipitation of the solubilized drugs once administered to the patient or when otherwise diluted in an aqueous environment. Complex drug carriers, such as liposomes have limited utility due to the unstable nature of the carrier particles and the preferential uptake and localization of liposomal drugs to the reticuloendothelial system, namely, the liver and spleen. Conventional Solvents and solubility enhancers can be toxic and irritating when injected into humans, such that the use of this solubilization approach is largely restricted to therapies for acute, life threatening diseases where medical experts are constantly in attendance to administer palliative treatments to counteract the adverse effects of the solvents/solubility enhancers. Water miscible solvents/solubility enhancers also possess the undesirable feature of allowing the drug to rapidly precipitate when an aqueous environment is contacted.
When the aqueous solubility of a drug candidate is inadequate to permit solution formulations, solubility enhancers are often employed to improve solubility. The use of solubility enhancers can increase the solubility by several orders of magnitude. Some commonly used solubility enhancers are propylene glycol, polyethylene glycols, ethanol and sorbitol. The addition of a co-solvent can increase solubility of hydrophobic molecules by reducing the dielectric constant of the solvent. Some problems with the use of solubility enhancers are precipitation of the drug with dilution of solvent mixture and tissue damage or pain upon injection. This dilution occurs after administration of the drug into the body. Generally polyethylene glycol (PEG) is an excipient of choice based on its good solubilization properties and overall acceptability in terms of side-effect profile. Side effect profile of PEG was discussed by Pang S, N. J in Final report on the safety assessment of polyethylene glycols (PEGs) reported in Journal of American College of Toxicology (1993), 12, 429-457.
WO 9518603 discloses the property of soluble polyvinylpyrrolidone increasing the solubility of drug without negatively affecting the adhesivity of the composition or the rate of drug delivery from the pressure-sensitive adhesive composition.
WO 03064656 discloses the biotin carboxyl carrier protein (BCCP), as a protein folding marker and protein solubility enhancer in the orientated surface capture of products of heterologously expressed genes. Methods for increasing the solubility of proteins and determining the folded state of a protein are also disclosed in this reference. In addition the nucleic acid molecule encoding the biotinylation domain of the tag moiety can be used to increase the proportion of clones in a library that express the protein of interest.
WO 03028589 discloses the polymeric compositions having improved capability of solubilizing a drug in a hydrophilic environment to form a solution, which comprises a biodegradable polyester oligomer; and biodegradable AB-type, ABA-type, or BAB-type block copolymers and method of uses thereof.
Cheng Yiyun et al., in European Journal of Medicinal Chemistry (2005), 40(12), 1390-1393 discusses the use of polyamidoamine dendrimers as solubility enhancers in the pharmaceutical preparation of Ketoprofen, wherein it states experimentally that the solubility of ketoprofen in the dendrimer solutions was proportional to dendrimer concentration.
Ming-Thau Sheu et al., in Journal of controlled release (2003), 88(3), 355-368 discusses the influence of micelle solublization by tocopheryl polyethylene glycol succinate on solubility enhancement and percutaneous penetration of estradiol. Results of this study show that the solubility of estradiol was improved in the presence of tocopheryl polyethylene glycol succinate through micellar concentration.
The present invention provides a novel solubility enhancer, which is capable to enhance the solubility of the partially soluble drugs and also avoid the limitation associated with the prior arts. Further the present invention provides an alternative method for the preparation of desirable formulations of such partially soluble drugs employing said novel solubility enhancer.